The invention pertains to a dosage form for delivering liquid, active agent formulations. In particular, it pertains to dosage forms that permit the controlled release of liquid, active agent formulations from gelatin capsules and methods for converting gelatin capsules into controlled release dosage forms.
Osmotic dosage systems comprising means for delivering a solid drug formulation by displacing physically the solid drug formulation from the osmotic system are known to the prior art in U.S. Pat. Nos. 4,327,725; 4,612,008; 4,765,989; and 4,783,337.
An osmotic system comprising means for displacing physically a liquid drug formulation from an osmotic system is known to the prior art in U.S. Pat. No. 4,627,850. U.S. Pat. No. 3,995,631 describes a dosage form having an impermeable flexible bag containing a liquid drug formulation surrounded by an osmotic layer. U.S. Pat. No. 4,203,440 describes a somewhat similar configuration in which a semipermeable layer in which is dispersed an ion exchange resin forms an osmotic layer surrounding a flexible bag from which drug is dispensed. U.S. Pat. No. 4,627,850 describes a capsule surrounded by an osmotic layer and outer, semi-permeable layer to dispense drug from the capsule upon expansion of the osmotic layer. U.S. Pat. No. 5,324,280, which is incorporated herein by reference, describes a gelatin capsule filled with a liquid drug formulation wherein the capsule is surrounded by an osmotic layer and an outer, semipermeable layer. Upon imbibing fluid that passes through the semipermeable membrane, the osmotic layer expands and forces the liquid drug formulation from an exit passageway formed in the end of the dosage form. While the foregoing system of U.S. Pat. No. 5,324,280 may provide controlled release of the active agent in particular circumstances, its use with gelatin capsules has not been entirely satisfactory for wide application.
In one aspect, the invention comprises a dosage form comprising (a) a gelatin capsule containing a liquid, active agent formulation; (b) a multilayer wall superposed on the gelatin capsule comprising, in outward order from the capsule: (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and (c) an orifice formed or formable through the wall.
In another aspect, the invention comprises a dosage form comprising a gelatin capsule containing a liquid, active agent formulation, the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semipermeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall.
In yet another aspect, the invention comprises a method of converting a gelatin capsule containing a liquid, active agent formulation into a controlled release dosage form which comprises forming a composite wall on the gelatin capsule by sequentially forming a barrier layer on the external surface of the gelatin capsule, an expandable layer on the barrier layer and a semipermeable layer on the expandable layer. An exit orifice may be formed in the wall directly, as by drilling, e.g., such as with a laser, or the exit orifice may be formed by sequentially forming an opening in the composite wall having a diametric dimension greater than the desired final diameter of the exit orifice, plugging the hole with a material in which the exit orifice may be formed, and then forming an exit orifice in the plug.
In still another aspect, the invention comprises a method of manufacturing a controlled release dosage form comprising a gelatin capsule containing a liquid, active agent formulation, which method comprises the steps of (1) forming a barrier layer surrounding the gelatin capsule containing a liquid, active agent formulation; (2) forming an expandable layer surrounding the barrier layer-gelatin capsule; (3) removing a portion of the expandable layer in an area in which an exit orifice is to be located without compromising the integrity of the barrier layer in the area; (4) forming a semipermeable layer surrounding the intermediate dosage form prepared through step (4); and forming an exit orifice in the area exposing at least a portion of the gelatin capsule. One or more of the layers may be formed by coating.
In yet another aspect, the invention comprises a dosage form comprising a gelatin capsule containing a liquid, active agent formulation, the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semipermeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall, wherein the barrier layer forms a seal between the expandable layer and the environment at the exit orifice.
In another aspect, the invention comprises a dosage form comprising a gelatin capsule containing a liquid, active agent formulation, the gelatin capsule being surrounded by a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting a portion of the barrier layer, a semipermeable layer encompassing at least the expandable layer, and an exit orifice formed or formable in the dosage form extending from the external surface of the gelatin capsule to the environment of use. The expandable layer may be formed in one or more discrete sections, such as for example, two sections located on opposing sides or ends of the gelatin capsule.